Abstract Cardiovascular disease (CVD) is the major cause of morbidity and mortality in the US and globally. Despite established risk factors for CVD, many cases remain unexplained. Cadmium is a heavy metal that has been shown to damage vascular tissues, induce endothelial dysfunction and promote atherosclerosis in animal and mechanistic studies. Epidemiologic studies have linked cadmium to cardiovascular endpoints such as hypertension, peripheral arterial disease, and cardiovascular mortality. Establishing cadmium as a cardiovascular risk factor, however, has been limited by the lack of prospective incidence studies. In addition few studies have had sufficient statistical power to investigate the association among never smokers to alleviate serious concerns about potential confounding by tobacco smoking. The objective of this proposed study is to investigate the association between incident cardiovascular outcomes and cadmium exposure at levels that are relevant to the general population among never-smokers. Human exposure to cadmium occurs primarily via diverse food types and cigarette smoke. Following intake, cadmium is stored predominantly in the kidney, where it remains for decades (half-life: 10-30 years). A small portion of cadmium is slowly excreted in the urine, making urinary cadmium a well-established biomarker of long-term exposure. We will leverage existing samples and data from the 19,000+ never-smoking participants in the prospective population-based Danish Diet Cancer and Health Cohort which recruited participants 1993-1997 and collected urine at that time. We will include demographic, behavioral, and clinical data from up to 20 years of follow-up to prospectively evaluate the association between cadmium exposure and clinical cardiovascular events. Using a case-cohort study design we will select cases of stroke (N=549), acute myocardial infarction (N=641), and heart failure (N=761), and a comparison subcohort of 600 men and 600 women. Trace metals, creatinine, osmolality, and cotinine will be analyzed in baseline urine samples. As a secondary Aim, we will apply mediation analyses using a counterfactual framework based approach to estimate the extent to which cadmium?s influence on stroke, heart failure, and acute myocardial infarction might be mediated via hypertension, hypercholesterolemia, and diabetes. Results from the mediation analysis may help to identify additional targets for intervention as well as aid in understanding the role of cadmium in the pathophysiology of these CVD events. Our proposed research will be one of the first studies to quantify the association between cadmium and incidence of cardiovascular disease in a longitudinal study with a never-smoking cohort. Sources of cadmium in the environment are well known, including phosphate fertilizers; given widespread cadmium exposure, and that cadmium exposure via food can be lowered by regulating fertilizer, the identification of cadmium as a cardiovascular risk factor can have major implications for the prevention and control of cardiovascular disease.